Assessing the reporting quality of adult neuro-oncology protocols, abstracts, and trials: Adherence to the SPIRIT and CONSORT statements

Abstract Background Comprehensive and transparent reporting of clinical trial activity is important. The Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) 2013 and Consolidated Standards of Reporting Trials (CONSORT) 2010 statements define the items to be reported in clinical trial protocols and randomized controlled trials, respectively. The aim of this methodological review was to assess the reporting quality of adult neuro-oncology trial protocols and trial result articles. Methods Adult primary and secondary brain tumor phase 3 trial protocols and result articles published after the introduction of the SPIRIT 2013 statement, were identified through searches of 4 electronic bibliographic databases. Following extraction of baseline demographic data, the reporting quality of independently included trial protocols and result articles was assessed against the SPIRIT and CONSORT statements respectively. The CONSORT-A checklist, an extension of the CONSORT 2010 statement, was used to specifically assess the abstract accompanying the trial results article. Percentage adherence (standard deviation [SD]) was calculated for each article. Results Seven trial protocols, and 36 trial result articles were included. Mean adherence of trial protocols to the SPIRIT statement was 79.4% (SD: 0.11). Mean adherence of trial abstracts to CONSORT-A was 75.3% (SD: 0.12) and trial result articles to CONSORT was 74.5% (SD: 0.10). Conclusion The reporting quality of adult neuro-oncology trial protocols and trial result articles requires improvement to ensure comprehensive and transparent communication of planned neuro-oncology clinical trials and results within the literature. Raising awareness by clinical triallists and implementing mandatory evidence of proof of adherence by journals should improve reporting quality.


clinical trial | CONSORT-A | CONSORT | SPIRIT
Clinical trials are designed to investigate the comparative effectiveness (superiority or noninferiority of a therapeutic option against another) in order to allow new treatment recommendations to be made. 1 Randomized controlled trials (RCTs) are generally regarded as the "gold standard" methodological approach, by isolating the influence of the intervention in question on outcome, through a process of randomization to treatment arm. 2 However, without comprehensive and transparent reporting of the planned methods (trial protocol) and results (trial results abstract and article), critical review and comparative analysis may be compromised.To this end, efforts have been made to standardize the reporting of these components with the publication of statements that describe the items to be reported on.
The Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) 2013 guidance provides evidence-based recommendations for the minimum items that should be included when drafting a clinical trial protocol for an

Assessing the reporting quality of adult neuro-oncology protocols, abstracts, and trials: Adherence to the SPIRIT and CONSORT statements
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https:// creativecommons.org/licenses/by/4.0/),which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.interventional clinical trial. 3The checklist includes 51 items.Adherence to SPIRIT ensures that all critical methodological aspects of the design of a clinical trial are addressed a priori.
The Consolidated Standards of Reporting Trials (CONSORT) statement, most recently updated in 2010, is an evidence-based, minimum set of recommendations for the reporting of randomized trials 4 and is endorsed by over 600 medical journals. 5,6The statement includes 25 items focused on reporting how a trial was designed, analyzed, and interpreted, with the overall aim of improving transparency of trial reporting.There are extensions of the CONSORT statement, notably CONSORT-A, which details specific considerations for the reporting of trial abstract items. 7aken together, the SPIRIT and CONSORT statements offer globally recognized reporting guidance to clinical triallists seeking to effectively communicate their planned and completed RCT.If a trial protocol or trial results article is not reported to these standards, the ability of a trial to inform clinical decision-making could be hampered.This creates difficulty, not only for the clinical triallist conducting the study, but for those seeking to interpret its results, for instance, other investigators including researchers, patients, funders and sponsors, ethics committees and institutional review boards, trial registries, and policymakers/ regulators. 3The simplicity of a checklist allows both the author and anyone critiquing the work, to identify these items of importance.
The standard of reporting quality in adult neurooncology trial protocols and clinical trial results has not been assessed to date.Therefore, the aim of this review was to assess the reporting quality of adult, phase 3 neurooncology trial protocols and trial result articles (concerning adult primary and secondary brain tumors) published since 2014 onwards, in line with the SPIRIT statement introduction in 2013 and the CONSORT statement update in 2010.In doing so, we aim to raise awareness of these tools, for both clinical triallists, and those seeking critical review of the neuro-oncology clinical trial literature.

Information Sources
A detailed search strategy was developed to identify adult, phase 3 neuro-oncology RCTs from the published literature, since 2014.The following electronic bibliographic databases were searched: PubMed, EMBASE, CINAHL, and the Cochrane central register of controlled trials.The complete search strategies are provided in Supplementary Appendix 1.

Eligibility Criteria
For the purposes of this methodological review, a sample of neuro-oncology clinical trial protocols and clinical trial result articles was required for subsequent analysis.The 2 article types did not need to be linked as pertaining to the same study and were evaluated separately.Therefore, the inclusion criteria for eligible studies were specified as published clinical trial protocols and clinical trial result papers (concerning phase 3 RCTs), that describe cohorts of adults (minimum 10 patients) with an intracranial tumor (glial, meningioma, or cerebral metastases), receiving interventions including perioperative care, surgery, radiotherapy, pharmacotherapy, or any combination of the above.Only full-text articles written in the English language (due to limitations of translation services) and published after January 1, 2014 were eligible for inclusion.The full eligibility criteria are provided in Supplementary Appendix 2.

Study Selection and Data Extraction
Search results were downloaded from their respective online databases, and a file for each was uploaded to the online platform Rayyan, 8 for the purposes of deduplication and screening.All potentially eligible titles and abstracts were screened by 2 review authors (J.S.S. and A.P.).For those appearing to meet the eligibility criteria, or for those where a decision could not be made based on title and abstract alone, full-text copies were obtained.All fulltext articles were then screened against the eligibility criteria by the same 2 review authors (J.S.S. and A.P.).Any titles which did not achieve concordance were highlighted within the platform, discussed, and resolved between the 2 review authors in person or escalated to the senior review author (C.P.M.).
Data were extracted independently from all eligible articles into a custom-designed and piloted data extraction spreadsheet in Microsoft Excel by 2 review authors (J.S.S. and A.P.).The first 10% of included articles were crosschecked for concordance, and if less than 5% variation in extracted data existed, data extraction proceeded without question.
The following study demographic data were extracted: Surname and country of first author, year, and journal of publication plus associated impact factor (as of 2021), protocol or trial title, phase intervention being carried out, and tumor type studied.In cases where multiple tumors were studied, the primary tumor type was recorded.

Assessment of Reporting Quality
Reporting quality of trial protocols was assessed against the SPIRIT 2013 statement checklist which has 51 items (Supplementary Appendix Table 3). 9A single point was awarded for adequate reporting of an item in the manuscript or supplementary material, as judged by the review author (Yes = 1 point, No = 0 point).The maximum score was 51 as all items on the SPIRIT checklist were applicable to protocols eligible for inclusion in this review.
Reporting quality of included clinical trial result articles were assessed against the CONSORT-A and CONSORT statement checklists.CONSORT-A checklist included 17 items (Supplementary Appendix 4) and CONSORT checklist included 37 items (Supplementary Appendix 5).
A single point was awarded for adequate reporting of an item in the manuscript or supplementary material, as judged by the review author (Yes = 1 point, No = 0 point).

Neuro-Oncology Neuro-Oncology Practice
For studies where an item on the checklist was not applicable (N/A), the maximum score attainable for that paper was reduced by one point.This was to remove penalization for non-applicable requirements.For example, item 11b "Similarity of interventions-If relevant, description of the similarity of interventions" was only applicable if the trial had 2 different interventions which were deemed similar in comparison to one another.If the trial had 2 interventions that were deemed dissimilar item 11b would receive N/A for that trial. 10Additionally, item 14b on the CONSORT checklist "Why the trial ended or was stopped" was only applicable for trials that ended or stopped before their natural conclusion. 10In conjunction with the accompanying explanation and elaboration document, if the trial was not ended or stopped early the trial would receive N/A for that question on the checklist.Furthermore, item 17b "For binary outcomes, presentation of both absolute and relative effect sizes is recommended" 10 was only relevant for trials with binary outcomes.In this review, none of the trials had binary outcomes so all trials received N/A for this item on the checklist.

Statistical Analysis
Descriptive analysis was used to calculate the proportion (shown as a percentage) of SPIRIT statement items that were adequately reported in protocols.Mean values are presented alongside the standard deviation (SD).The same analysis was carried out on the clinical trial results from articles using the CONSORT-A and CONSORT 2010 statement checklists.Analysis was carried out on Microsoft Excel.

Study Characteristics
Forty-three articles were included in this review, of which 7 were trial protocols and 36 were phase 3 clinical trial result articles.The included trial protocols and phase 3 clinical trial result articles were independent of one another.The search, screening, and selection results are summarized in Figure 1.Most of the included protocols described planned phase 3 trials, apart from a single study that related to a phase 1/3 trial.Of the included protocols, 43% (n = 3) had a first author affiliated with an institution in North America.Publication in BMC Cancer, which endorses the use of the SPIRIT statement, accounted for 43% (n = 3) of the protocols. 11Table 1 provides an overview of the included protocols.
Over half of the clinical trial result articles had a first author affiliated with an institution in the United States (53%, n = 19), while 25% (n = 9) were affiliated with an institution in Europe, and the remainder from the rest of the world 22% (n = 8).Publication in the Journal of Clinical Oncology accounted for 36% (n = 13) of the clinical trial articles, while 25% (n = 9) of trials were published by the Lancet publication group, including the Lancet and Lancet Oncology.Glioblastoma was the study subject for 42% (n = 15).Table 2 provides an overview of the included clinical trial articles.

Quality of Reporting as Per SPIRIT 2013 Statement
Seven protocols were included in this review and assessed against the SPIRIT statement.An average adherence rate of 79.4% (SD: 0.11) was observed.The range of compliance with the 51 items in the checklist was 32/50 to 46/50.There was one "non-applicable" question in the SPIRIT statement regarding item 33 "biological specimens." If a protocol was not collecting biological specimens for analysis it would not be applicable for that protocol to explain the methods used to store such specimens.All included protocols reported the administrative information for the protocol, described the background and rationale, and reported the study setting.Only 57.1% (n = 4) of the protocols included explained the choice of comparators.Although all 7 protocols described the planned interventions in each group, including administration methods, only 71.4% (n = 5) of protocols described criteria for discontinuing or modifying the allocated interventions as well as strategies to improve protocol adherence.Furthermore, only one protocol listed concomitant care and interventions that would be allowed or prohibited throughout the trial.The assignment of interventions, including details on sequence generation, was reported in 57.1% (n = 4) of protocols and allocation and implementation in only 42.9% (n = 3).Only 28.6% (n = 2) of protocols reported whether blinding took place.
All 7 protocols reported planned statistical analysis and a further 85.7% (n = 6) of trials described any planned additional analyses.However, all protocol authors failed to report details regarding protocol nonadherence and any statistical methods to handle missing data in the population analyzed.A summary of the adherence rates for each item in the SPIRIT 2013 checklist can be seen in Figure 2 and in Supplementary Appendix 6.

Quality of Reporting as per CONSORT-A checklist
Thirty-six clinical trial abstracts from the results article were assessed against the CONSORT-A statement.Average adherence rate with the checklist was 75.3% (SD: 0.12).The range of compliance with items from the checklist was 6/17 to 15/17.All items on the CONSORT-A checklist were deemed applicable to every abstract.Randomization was identified in the title in 80.5% (n = 29) of trial abstracts, and corresponding authors' details and trial design were reported in 88.8% (n = 32) of included abstracts.All abstracts (n = 36) accurately reported the trial objectives, interventions, and outcomes.
Randomization, including the strategy to allocate participants to interventions, was only reported in 38.9% (n = 14) of abstracts, and information on blinding was reported in only 27.8% (n = 10) of abstracts.Trial status was reported in 44% (n = 16) of included abstracts.
Primary outcome, estimated effect size and precision, conclusions, and result interpretation were reported accurately in all abstracts.Details on trial registration were reported in only 38.9% (n = 14) of the included trial abstracts and only 27.7% (n = 10) mentioned trial funding.A summary of the compliance rates of each item on the

Neuro-Oncology Neuro-Oncology Practice
CONSORT-A checklist can be seen in Figure 3 below and in Supplementary Appendix 7.
The included abstracts were also analyzed based on their year of publication.A two-sample t-test was performed to compare trials published in 2013-2017 (group 1, n = 25) to trials published between 2018 and 2022 (group 2, n = 11).There was no significant difference in concordance rate (%) between group 1 (mean = 75.6%,SD: 0.10) and group 2 (mean = 74.3,SD: 0.16), P = .76.

Quality of Reporting as per CONSORT 2010 Statement
Thirty-six phase 3 RCTs were included in this analysis.After accounting for non-applicable items, the mean score was 74.5% (SD: 0.10) with a range of 22/34 to 31/34.Identification of the trial as randomized in the title was present in 80.5% (n = 29).All included trials discussed the scientific background of their paper and highlighted any objectives or hypotheses clearly.88.8% (n = 32) of trials discussed the trial design, including allocation ratio, with points only being awarded if both the allocation ratio and design were mentioned.Only 13.9% (n = 5) of trials discussed any important changes that were made after the trial commenced.If no changes were made but the trial explicitly stated this, then they would also receive a "Yes." All trials described primary and secondary outcome measures, including how these measures would be assessed, but no included trials reported whether changes had been made to the objectives after the trial had commenced.
Reporting on randomization methods was varied across the included RCTs.While 80.5% (n = 29) of studies identified the trial as randomized in the title, only 69.4% (n = 25) described the method used to generate the randomization sequence in the study.Furthermore, only 22.2% (n = 8) trials described the implementation of randomization, including who generated the randomized allocation sequence, who enrolled the participants, and who assigned the interventions.Information on blinding was also inadequate, only being reported in 25% (n = 9) of studies.
For 91.2% (n = 33) of included trials, the item questioning the similarity of interventions was deemed not applicable because many trials had interventions that were not comparable.All of the included trials did not include binary outcomes, hence all received N/A for this item against the CONSORT checklist.
Trial generalizability was reported in all included trials.However, the trial limitations, including sources of bias and misinterpretation were reported in only 69.4% (n = 25) of included trials.All articles (n = 36) included descriptions of funding and the trial registration number.Only 69.4% (n = 25) reported where the full trial protocol could be found.A summary of compliance rate can be seen in Figure 4 below and in Supplementary Appendix 8.
The included phase III trials were also analyzed based on the year of publication.A two-sample t-test was performed to compare trials published in 2013-2017 (group 1, n = 25) to trials published between 2018 and 2022 (group 2, n = 11).There was no significant difference in concordance rate (%) between group 1 (mean = 75.5%,SD: 0.08) and group 2 (mean = 72.0%,SD: 0.12), P = .31.It was also investigated whether the journal where a phase III trial was published in influenced the reporting quality.A Pearson correlation coefficient was computed to assess for a linear relationship between journal impact factor and the concordance  rate (%) to the CONSORT checklist.There was a small positive correlation between the 2 variables, r = 0.28 (n = 36).However, this relationship was not statistically significant (P = .10).

Summary of Key Results
The quality of reporting as per SPIRIT 2013 statement displayed inadequate reporting of the assignment of interventions, with details on sequence generation being reported in only 57.1% (n = 4) protocols and allocation and implementation in only 42.9% (n = 3).Blinding was reported in 28.6% (n = 2) of the included protocols.All abstracts (n = 36) accurately reported the trial objectives, interventions, and outcomes using the CONSORT-A statement.Randomization, including the strategy to allocate participants to interventions, was only reported in 38.9% (n = 14) of abstracts and information on blinding was reported in only 27.8% (n = 10) of abstracts.The quality of reporting as per CONSORT 2010 statement was 100% (n = 36) when trials discussed the scientific background to their paper and highlighted any objectives or hypothesis clearly.However, only 69.4% (n = 25) described the method used to generate the randomization sequence in the study.Trial limitations, including sources of bias and misinterpretation, were reported in only 69.4% (n = 25) of included trials.

Discussion
RCTs are the "gold standard" methodological tool used to provide evidence of comparative effectiveness, and established guidance exists to facilitate the reporting of both trial protocols and clinical trial results.This is the first analysis of the quality of reporting of adult neuro-oncology clinical trial protocols and clinical trial results.The study highlights the common reporting deficiencies.

Trial Protocols and the SPIRIT 2013 Statement
The SPIRIT 2013 statement serves as a framework of important items to include in a clinical trial protocol, and to facilitate comprehensive and transparent reporting.Administrative information including the title, registration, protocol version, funding, and responsibilities was found to be reported in the included protocols.All protocols also provided a description of funding sources so the reader can objectively assess and evaluate any potential conflicting interests. 3lmost all protocols described the research question and justified the need for the trial, however not all protocols explained the choice of comparators.Only 42.9% (n = 3) of protocols included reasoning for comparators, highlighting an area where improvements can be made in future protocols.
All protocols reported the trial design in sufficient detail to enable replication.This is important in order to provide a context for a protocol and to ensure participants in the study are appropriate, fulfill certain specifications, and are representative of the target population.Many protocols did not discuss strategies to improve adherence to intervention protocols, and any procedures for monitoring adherence. 3Relevant concomitant care and interventions that are permitted or prohibited during the trial were very poorly reported, with only one protocol discussing it.Concomitant care is an important element of any protocol as there should only be one variable intervention between the trial and control groups  and concomitant care can act as a confounding variable or co-intervention if not properly controlled for. 3andomization details were poorly reported in the included protocols.Randomization is a cornerstone of the study design and specific standards must be upheld when reporting the associated methodology. 12Only a minority of protocols adequately reported the methods and mechanisms used to generate the randomized allocation sequence.Failing to report this information can hinder a reader's ability to measure the magnitude and precision of the treatment effect, as well as any selection bias. 13Similarly, only a small proportion of protocols adequately reported details on blinding.When reporting prospective clinical trial protocols efforts should be made to report succinct and compressive details on the randomization process and, if applicable, blinding.
Methodological processes, including description of study setting, as well as eligibility criteria were reported particularly well throughout the included protocols.Many protocols also reported ways to promote participant retention and complete follow-up which is important to maximize completeness of data collection. 3Statistical methods used to analyze data were described in most protocols, with justifications for choice of statistical methods and any comparisons which had been made.There was very poor compliance with reporting on any instances of protocol nonadherence, which allows speculation regarding possible missing data which might have an impact on the outcomes reported.Prospective clinical trial protocols should make effort to comment on how they will manage protocol nonadherence and remove speculation from the reader.
Ethical approval and important trial modifications are adequately reported in most protocols.Ethical approval is a universal requirement in clinical research, 3 however for completeness all protocols should report how they applied for approval, the granting body and declare all protocol amendments post ethical approval.
Although journals impose strict word count limits on authors when publishing abstracts, key information like randomization and blinding should be reported to the same level as the background, objectives, aims, methods, and results.If the full trial mentioned funding at the end of the trial manuscript, but not in the abstract that paper would receive a "No" against the CONSORT-A checklist.Due to the significant implications of outcomes from neurooncology clinical trials, declaring any funding or conflict of interest is very important to ensure transparency.

Clinical Trial Results and the CONSORT 2010 Statement, Including CONSORT-A
The fundamental purpose of the CONSORT statement is to improve the quality of reporting and ultimately transparency of randomized trials.The CONSORT-A checklist, the abstract-specific extension of CONSORT 2010 statement was used to assess the included abstracts.
In the included trials the reporting of background, aims, and objectives, as well as what previous research supported the rationale behind the intervention was particularly high.The methodology in these trials was reported adequately and included a comprehensive description of all elements of the trial allowing transparency and easy replication of the study conditions.The trial interventions were described in detail and important variables such as dosage, route of administration, and procedures involved were present to facilitate easy replication.This theme was consistent with the included abstracts where objectives, interventions, and outcomes were well reported and with sufficient detail to facilitate replication.
In many of the included RCTs, the settings and locations of the trial were not reported.Sample size calculations are useful as it provides a metric by which readers can judge if a trial reached its planned size, 14 was also reported poorly.None of the included trials reported on the changes to the trial outcomes.Similarly, trial status was only reported in 16 trial abstracts (44%), with authors consistently failing to mention whether the trial was ongoing, closed to recruitment, or closed to follow-up.For future trials, the addition of a sentence mentioning if any trial changes had been made and the status of the trial can remove unnecessary ambiguity and should be considered.
A key flaw in the reporting of many included trials concerned randomization.Evidence shows errors in randomization sequence generation are common and can lead to invalid conclusions if errors are not discovered. 12Due to this, efforts should be made to be as informative and transparent about randomization details when reporting a trial.Blinding, an important tool in protecting against potential bias was also reported poorly.This theme was also very common throughout the included abstracts, being 2 of the most poorly reported areas across both trials and abstracts.As per the CONSORT explanation and elaboration, document 10 authors had to describe the randomization and blinding process and not merely state that randomization and blinding took place to score a "Yes" for that checklist item.While it is not our primary aim to highlight specific areas that need greater awareness across the CONSORT and CONSORT-A checklists, these 2 areas are particularly poor and prospective authors should report these details in full.
Interpretations and results of the included trials were well reported with many trials discussing how the new findings were relevant to other RCT's.This was consistent with the included abstracts where authors consistently reported the overall results of the trial.However, although the number of participants randomized to each group were reported well across the included trials, many abstracts failed to mention this.Authors should highlight this in future abstracts to improve reporting standards.
Trial limitations were not reported in several trials.Limitations should be discussed in full, as well as any methods used to overcome said limitations.Although CONSORT-A does not encourage reporting of trial limitations, harms, and adverse effects are required to be reported.The majority of included abstracts reported important adverse effects or side effects in enough detail to receive a "Yes" on the CONSORT-A checklist.Similarly, adverse effects were well discussed in the included trials.
Trial funding was reported in most trials.Financial support, if any, should always be disclosed to allow readers to make their own judgment on whether a funding source may have influenced a result.However, in the included abstracts funding was poorly reported.When assessing the reporting quality of abstracts, funding had to be directly mentioned in the abstract to score a "Yes" against the CONSORT-A checklist.

Figure 1 .
Figure 1.Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Flow Chart -16 685 articles identified following initial search.Screening of titles and abstracts identified 102 articles for full-text review.Forty-three articles were included in the study.

France
sulfate for fatigue in primary brain tumors patients: An ANOCEF trial (DXA) Cancer trial with nimotuzumab, an anti-epidermal growth factor receptor monoclonal antibody in the treatment of newly diagnosed adult glioblastoma POST-OPERATIVE RADIOSURGERY COMPARED WITH WHOLE BRAIN RADIO-THERAPY FOR RESECTED METASTATIC BRAIN DISEASE: COGNITIVE FUNCTION OF LONG-Oncology Whole brain radiation therapy (WBRT) in addition to radiosurgery (SRS) in patients with 1 combination therapy versus standard temozolomide therapy in patients with newly diagnosed glioblastoma with methylated MGMT promoter (CeTeG/NOA-09): a randomized, open-label, phase 3 Journal of Neurooncology Trial of hyperfractionated radiotherapy (RT) and BCNU vs. standard RT and BCNU for malignant Oncology Phase III study of radiation therapy (RT) with or without procarbazine, CCNU, and vincristine (PCV) in low-grade glioma: RTOG 9802 with Alliance, ECOG, and SWOG.Oncology radiation therapy (RT) and O⁶-benzylguanine + BCNU versus RT and BCNU alone and methylation status in newly diagnosed glioblastoma and gliosarcoma 3 Glioblastoma and Gliosarcoma

Figure 4 .
Figure 4. Compliance rate (%) to CONSORT 2010 Statement Checklist.Note item 17b was deemed "not-applicable" to any of the included trials.

Table 1 .
Overview of included protocols assessed using SPIRIT statement

Table 2 .
Overview of included phase III trials and abstracts assessed using the CONSORT 2010 statement and CONSORT-A checklist Compliance rate (%) to SPIRIT 2013 statement.Note that item 17c was deemed "not applicable" to any of the included protocols.